Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and the primary infectious cause of serious birth defects in newborns. HCMV has long been recognized as an infectious threat to the fetus, particularly in women without HCMV immunity and who have a primary HCMV infection during pregnancy. The major source of infection for pregnant women are children with subclincal HCMV infection. Children that become infected congenitally or perinatally shed virus for longer periods of time and at higher titers than people that acquire HCMV later in life. The mechanism(s), why children who acquire the virus early in prenatal or post-natal life shed the virus longer and in higher titers are not known. Considering the severe health risks associated with congenital HCMV infection, breaking the chain of transmission from subclinically infected children to pregnant women to fetuses would have important benefits for human health. This requires a better understanding of virus-host interactions in very young children as compared to adults. For ethical reasons, studies in newborns are very limited. Thus, we propose to develop a nonhuman primate model of infant HCMV infection by orally infecting infant macaques with rhesus CMV (RhCMV) (Aim 1). A model of HCMV pathogenesis in adult macaques has been developed and closely mimics HCMV infection in humans. The establishment of an infant model of RhCMV infection will provide us with the opportunity to define differences in specific immune responses to RhCMV infection between infants and adults while keeping the virus inoculum, the dose, and the route of transmission constant. The underlying assumption is that long-term virological outcome in HCMV infected patients depends on the earliest virus-host interactions. As the infant immune system is less mature, the overall HCMV response is less likely to control virus replication. HCMV-specific CD4+T cells have been implicated to play an essential role in the control of virus replication. Thus, we present the hypothesis that a limited functional capacity of infant CD4+T cells, as assessed by reduced IFN-g production, combined with higher frequencies of regulatory T cells in infants interfere with the development of effective HCMV-specific CD4+T cells (Aim 2). This hypothesis will be tested in the infant macaque model of RhCMV infection established in Aim 1. The results of the proposed studies should be of broader importance for understanding infant immune responses to other infectious agents and how to prevent a pathogenic outcome in children. Thus, a nonhuman primate model of infant HCMV infection would be a unique resource to test the efficacy and safety of pediatric antiviral therapies and HCMV vaccines. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and is the primary infectious cause of serious birth defects in newborns. Children with sublinical HCMV infection are the major source for HCMV infection in pregnant women because HCMV infected children shed virus for a longer time and at higher titers that people that acquire HCMV later in life. We propose to develop a nonhuman primate model of infant HCMV infection to advance our understanding of the age-related differences in HCMV pathogenesis in infants and adults with the longterm goal of breaking the chain of transmission from subclinically infected children to pregnant women to fetuses.